Process for producing solid dosage forms

ABSTRACT

Solid dosage forms containing at least one polymer binder, at least one active ingredient and, where appropriate, conventional additives, wherein a physiologically tolerated, water-swellable graft copolymer or a mixture of graft copolymers is employed as polymeric binder.

This is a Divisional application of application Ser. No. 09/268,719,filed on Mar. 17, 1999, now U.S. Pat No. 7,022,344 B1, the entiredisclosure of which is hereby incorporated by reference.

The invention relates to a process for producing solid dosage forms bymixing at least one polymeric binder and, where appropriate, at leastone active ingredient and, where appropriate, conventional additives toform a plastic mixture, and shaping. The invention particularly relatesto a process for producing solid pharmaceutical forms.

Classical processes for producing solid pharmaceutical forms, especiallytablets, are carried out batchwise and comprise a plurality of stages.Pharmaceutical granules represent an important intermediate therefor.Thus, for example, Bauer, Frömmig and Führer, “PharmazeutischeTechnologie”, Thieme Verlag, pages 292 et seq., reveal that drug formscan be obtained from the melt by dry granulation. The possibility ofproducing solidified melt granules either by melting and shocksolidification, by casting and comminuting or by prilling in spraytowers is described. One problem with these processes is the accurateshaping which is necessary for producing drugs. Irregular particles orfragments are often produced, so that the resulting shape by no meanscorresponds to customary drug forms, and granules therefore have onlylittle importance as a drug form on their own. Production of desiredsolid drug forms requires the use of further process steps such ascompression in tabletting machines. This is time-consuming and costly.

A considerably simpler continuous process for producing solidpharmaceutical forms has been known for some time and entails extrudinga solvent-free melt of a polymeric binder containing active ingredients,and shaping the extrudate to the required drug form, for example in acalender with molding rolls, see EP-A-240 904, EP-A-240 906, EP-A-337256, U.S. Pat. No. 4,880,585 and EP-A-358 105. It is possible in thisway to achieve specific shaping. The polymeric binders employed are, inparticular, polymers of N-vinylpyrrolidone or copolymers thereof, eg.with vinyl acetate.

Dosage forms based on polymers of this type have the disadvantage thatthey release the active ingredient relatively quickly. It is thereforeimpossible to produce slow-release dosage forms without takingadditional measures, for example applying a release-controlling coating.

It is an object of the present invention to provide dosage forms whichcan be produced by melt extrusion and are capable of slow release ofactive ingedient.

We have found that this object is achieved by using a physiologicallytolerated, water-swellable graft copolymer as polymeric binder.

The present invention therefore relates to a process for producing soliddosage forms by mixing at least one polymer binder, at least one activeingredient and, where appropriate, conventional additives to form aplastic mixture, and shaping, herein an in particular physiologicallytolerated, is water-swellable graft copolymer or a mixture of graftcopolymers is employed as polymeric binder.

The novel process makes it possible to produce solid dosage forms withvery slow release of active ingredient (“sustained release”, “slowrelease”) in a simple and cost-effective manner. Another surprisingadvantage of the novel process is that it is also possible, owing to thelow glass transition temperature of the graft copolymers which can beemployed (<90° C.), to prepare formulations of temperature-sensitiveactive ingredients under mild conditions. It is moreover possible toadjust the rate of release within a wide range by admixing polymers withrapid release, such as polyvinylpyrrolidone; copolymers ofpolyvinylpyrrolidone and vinyl acetate; cellulose ethers such ashydroxypropylcellulose or hydroxyethylcellulose; polyethylene glycols orethylene oxide/propylene oxide-block copolymers (e.g. the pluronicbrands of BASF AG); polyvinyl alcohols; partially hydrolyzed polyvinylalcohols or suitable low molecular weight substances such as sugaralcohols, sugars or salts.

Dosage forms mean herein all forms which are suitable for use as drugs,plant treatment compositions, human and animal foods and for deliveringfragrances and perfume oils. These include, for example, tablets of anyshape, pellets, granules, but also larger forms such as cubes, blocks(bricks) or cylindrical forms, which can be used, in particular, ashuman or animal foods.

The dosage forms obtainable according to the invention generallycomprise:

-   I 0-90% by weight, in particular 0.1-60% by weight (based on the    total weight of the dosage form) of an active ingredient,-   II 10-100% by weight, in particular 40-99.9% by weight, of the    polymeric binder and-   III where appropriate additives.

The polymers used according to the invention as binders are obtainablein a manner known per se by free-radical polymerization. Preparationtakes place, for example, by solution, precipitation, suspension oremulsion polymerization using compounds which form free radicals underthe polymerization conditions. It is preferred to employ in the novelprocess a graft copolymer obtainable by polymerization, initiated byfree radicals, of

-   a) a component selected from    -   a1) C₁-C₃₀-alkyl esters of an α,β-monoethylenically unsaturated        C₃-C₃₀-mono- or dicarboxylic acid. The C₁-C₁₈—, in particular        the C₁-C₈—, alkyl esters of these acids are preferred. Of these        acids, the C₃-C₈-mono- or dicarboxylic acids are preferred, such        as acrylic acid, methacrylic acid, dimethylacrylic acid,        ethacrylic acid, maleic acid, citraconic acid, methylenemalonic        acid, crotonic acid, fumaric acid, mesaconic acid and itaconic        acid, with acrylic acid and methacrylic acid being particularly        preferred,    -   a2) C₂-C₄-hydroxyalkyl esters of the acids mentioned under a1),    -   a3) amides, mono- or di-C₁-C₄-alkylamides and nitriles of the        carboxylic acids mentioned under a1),    -   a4) vinyl esters of C₁-C₁₈-monocarboxylic acids and    -   a5) vinylaromatic compounds, in particular styrene,-   b) oxygen-containing, preferably hydroxyl-containing polymers, in    particular also containing alkylene oxide units, as grafting base    and-   c) where appropriate a monomer which has at least two nonconjugated    ethylenically unsaturated double bonds.

It is also possible to employ a mixture of monomers a). It isfurthermore possible for the monomers a) to comprise up to 5% by weight,based on the total amount of monomers a), of an α,β-monoethylenicallyunsaturated C₃-C₈-carboxylic acid, in particular acrylic acid ormethacrylic acid.

It is possible to employ as monomers a) for preparing the graftcopolymers in particular methyl acrylate, ethyl acrylate, methylmethacrylate, ethyl methacrylate, hydroxyethyl acrylate, hydroxypropylacrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate,hydroxypropyl methacrylate, hydroxyisobutyl acrylate, hydroxyisobutylmethacrylate, monomethyl maleate, dimethyl maleate, monoethyl maleate,diethyl maleate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate,stearyl acrylate, stearyl methacrylate, behenyl acrylate, behenylmethacrylate, octyl acrylate, octyl methacrylate, acrylamide,methacrylamide, N-dimethylacrylamide, N-tert-butylacrylamide,acrylonitrile, methacrylonitrile, and vinyl acetate, vinyl propionateand styrene or mixtures thereof. Particularly preferred components a)are methyl acrylate, ethyl acrylate, methyl methacrylate, ethylmethacrylate, n-butyl acrylate, tert-butyl acrylate or mixtures thereof.

The grafting bases are preferably selected from:

-   b1) polymers containing alkylene oxide units. These include homo-    and copolymers of C₂-C₄-alkylene oxides, polytetrahydrofurans, the    products of the reaction of C₂-C₄-alkylene oxides with    C₁-C₃₀-alcohols, fatty acids, C₁-C₁₂-alkylphenols, primary or    secondary aliphatic C₂-C₃₀-amines, or mixtures thereof;-   b2) polyvinyl alcohols or copolymers of polyvinyl alcohol (PVA) and    vinyl acetate (VA) (partially hydrolyzed polyvinyl acetate),    preferably in the PVA:VA ratio of 95:5 to 10:90 by weight;-   b3) starch, cellulose and derivatives thereof, such as    methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose    and carboxymethylcellulose.

The copolymers of C₂-C₄-alkylene oxides may be either random copolymers,when mixtures of at least 2 alkylene oxides are polymerized, or blockcopolymers, when firstly one alkylene oxide, for example ethylene oxide,is polymerized and then another alkylene oxide is polymerized, e.g.propylene oxide. The block copolymers may, for example, belong to theAB, ABA or BAB type, where A can be, for example, a polyethylene oxideblock and B can be a polypropylene oxide block. These copolymers mayalso, where appropriate, contain n-butylene oxide and/or isobutyleneoxide units. The polyalkylene oxides contain at least three alkyleneoxide units in the molecule. The polyalkylene oxides can have, forexample, up to 50 000 alkylene oxide units in the molecule. Thepolytetrahydrofurans contain, for example, 3 to 200, preferably 3 to100, tetramethylene oxide units.

Compounds b) which are particularly preferably employed are, besides theabovementioned homo- or block copolymers of ethylene oxide and propyleneoxide, also ethylene oxide/propylene oxide copolymers with a randomstructure, and polyvinyl alcohol.

Examples of suitable alcohols for the products of the reaction ofalkylene oxides with alcohols (C₁-C₃₀-alcohols) are aliphaticmonoalcohols such as methanol, ethanol, n-propanol, isopropanol,n-butanol, n-octanol, 2-ethylhexanol, decanol, dodecanol, palmitylalcohol, cetyl alcohol and stearyl alcohol. However, it is also possibleto employ dihydric and polyhydric aliphatic alcohols, e.g. glycol,glycerol, erythritol, pentaerythritol and sorbitol. The alcohols arereacted in the molar ratio of 1:3 to 1:200 with at least oneC₂-C₄-alkylene oxide.

Further suitable polymers b1) containing alkylene oxide units areproducts of the reaction of fatty acids with alkylene oxides.Particularly suitable fatty acids are those which contain 8 to 10 Catoms in the molecule, for example lauric acid, myristic acid, stearicacid, palmitic acid, coconut fatty acid, tallow fatty acid and oleicacid.

Polymers b1) containing alkylene oxide units are moreover the productsof the addition of C₂-C₄-alkylene oxides onto C₁-C₁₂-alkylphenols suchas n-cetylphenol, n-octylphenol, isobutylphenol and methylphenol. Alsosuitable as component b) for preparing the graft copolymers are theproducts of the addition of C₂-C₄-alkylene oxides onto primary andsecondary C₂-C₃₀-amines such as di-n-butylamine, di-n-octylamine,dimethylamine and distearylamine. The molar ratio of amine to alkyleneoxide is from 1:3 to 1:200, and is preferably in the range from 1:3 to1:100. For preparing the adducts of alkylene oxides and alcohols,phenols, acids or amines, it is possible to add the alkylene oxides in aknown manner onto the abovementioned compounds simultaneously andsuccessively. Successive addition of alkylene oxides results in blockcopolymers. It may in some cases also be advantageous to cap the free OHgroups of the alkoxylation products with an endgroup. Endgroup cappingcan take place, for example, with an alkyl radical to form an ethergroup. For example, the alkoxylation products can be reacted with analkylating agent such as dimethyl sulfate. The terminal OH groups canalso be esterified where appropriate by reacting with carboxylic acids,e.g. acetic acid or stearic acid.

The graft copolymers can be modified by copolymerizing the monomers ormonomer mixtures of component a) with up to 5% by weight, preferably0.05 to 2% by weight, of one or more monomers of component c) which haveat least two nonconjugated ethylenically unsaturated double bonds in themolecule in the presence of component b). The components c) are normallyused as crosslinkers in copolymerizations. Examples of suitablecomponents c) are methylenebisacrylamide, divinylethyleneurea, esters ofacrylic acid and methacrylic acid with polyhydric alcohols, such asglycol diacrylate, glycerol triacrylate, glycol dimethacrylate, glyceroltrimethacrylate, and polyols esterified at least twice with acrylic acidand methacrylic acid, such as pentaerythritol and glucose. Suitablecrosslinkers which can also be employed as component c) aredivinylbenzene, divinyldioxane, pentaerythritol triallyl ether andpentaallylsucrose.

Components a) and b) are preferably employed in a ratio by weight in therange from 95 to 10:5 to 90, in particular 85 to 55:15 to 45.

The polymerization temperatures for producing the graft copolymers whichcan be employed according to the invention are normally in the rangefrom 30 to 200° C., preferably 40 to 110° C. Examples of suitableinitiators are conventional azo and peroxy compounds, and conventionalredox initiator systems such as combinations of hydrogen peroxide andreducing compounds, for example sodium sulfite, sodium bisulfite, sodiumformaldehyde sulfoxylate and hydrazine.

The graft copolymerization can also be carried out by exposure toultraviolet radiation, where appropriate in the presence of UVinitiators. Employed for polymerization with exposure to UV rays are thephotoinitiators and sensitizers normally considered for this purpose,such as benzoin and benzoin ethers, α-methylbenzoin or α-phenylbenzoin.It is also possible to use triplet sensitizers such as benzil diketals.Examples of sources of UV radiation used are, beside high-energy UVlamps such as carbon arc lamps, mercury vapor lamps or xenon lamps, alsolow-UV light sources such as fluorescent tubes with a high blue content.

The usual regulators can be employed to obtain low molecular weights,for example compounds which contain sulfur in bound form, such as alkylmercaptans.

The graft copolymers generally have K values of at least 7, preferablyfrom 10 to 100, in particular 20 to 100, particularly preferably 20 to35. The K values are determined by the method of H. Fikentscher,Cellulosechemie, volume 13, 58-64 and 71-74 (1932), in aqueous solutionor in an organic solvent at 25° C. and with concentrations between 0.1%and 5%, depending on the K value range.

Besides the polymeric binders which can be employed according to theinvention and are described above, it is possible to employ inparticular up to 30% by weight, based on the total weight of the binder,of other binders such as polymers, copolymers, cellulose derivatives,starch and starch derivatives. Suitable examples are:

Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) andvinyl esters, in particular vinyl acetate, copolymers of vinyl acetateand crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinylalcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),polyacrylates and polymethacrylates (Eudragit types), copolymers ofmethyl methacrylate and acrylic acid, polyacrylamides, polyethyleneglycols, cellulose esters, cellulose ethers, especially methyl celluloseand ethyl cellulose, hydroxyalkylcelluloses, especiallyhydroxypropylcellulose, hydroxyalkylalkylcelluloses, especiallyhydroxypropylethylcellulose, cellulose phthalates, especially celluloseacetate phthalate and hydroxypropylmethylcellulose phthalate, andmannans, especially galactomannans. Of these, polyvinylpyrrolidone,copolymers of N-vinylpyrrolidone and vinyl esters, poly(hydroxyalkylacrylates), poly(hydroxyalkyl methacrylates), polyacrylates,polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses areparticularly preferred.

The polymeric binder which can be employed according to the inventionmust soften or melt in the complete mixture of all the components in therange from 50 to 180° C., preferably 60 to 130° C. The glass transitiontemperature of the mixture must therefore be below 180° C., preferablybelow 130° C., in particular below 90° C. If necessary, it is reduced byconventional pharmacologically acceptable plasticizing auxiliaries. Theamount of plasticizer does not exceed 30% of the total weight of binderand plasticizer in order to form storage-stable drug forms which show nocold flow. However, the mixture preferably contains no plasticizer.

Examples of such plasticizers are:

long-chain alcohols, ethylene glycol, propylene glycol, glycerol,trimethylolpropane, triethylene glycol, butanediols, pentanols such aspentaerythritol, hexanols, polyethylene glycols, polypropylene glycols,polyethylene/propylene glycols, silicones, aromatic carboxylic esters(eg. dialkyl phthalates, trimellitic esters, benzoic esters,terephthalic esters) or aliphatic dicarboxylic esters (eg. dialkyladipates, sebacic esters, azelaic esters, citric and tartaric esters),fatty acid esters such as glycerol mono-, di- or triacetate or sodiumdiethyl sulfosuccinate. The concentration of plasticizer is generallyfrom 0.5 to 15, preferably 0.5 to 5, % of the total weight of themixture.

Conventional pharmaceutical auxiliaries, whose total amount can be up to100% of the weight of the polymer, are, for example, extenders andbulking agents such as silicates or diatomaceous earth, magnesium oxide,aluminum oxide, titanium oxide, stearic acid or its salts, eg. themagnesium or calcium salt, methylcellulose, sodiumcarboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch,potato flour, polyvinyl alcohol, in particular in a concentration offrom 0.02 to 50, preferably 0.20 to 20, % of the total weight of themixture.

Lubricants such as aluminum and calcium stearates, talc and silicones,in a concentration of from 0.1 to 5, preferably 0.1 to 3, % of the totalweight of the mixture.

Flowability agents such as animal or vegetable fats, especially inhydrogenated form and those which are solid at room temperature. Thesefats preferably have a melting point of 500° C. or above. Triglyceridesof C₁₂, C₁₄, C₁₆ and C₁₈ fatty acids are preferred. It is also possibleto use waxes such as carnauba wax. These fats and waxes may be admixedadvantageously alone or together with mono- and/or diglycerides orphosphatides, especially lecithin. The mono- and diglycerides arepreferably derived from the abovementioned fatty acid types. The totalamount of fats, waxes, mono-, diglycerides and/or lecithins is from 0.1to 30, preferably 0.1 to 5, % of the total weight of the composition foreach layer.

Dyes, such as azo dyes, organic or inorganic pigments or dyes of naturalorigin, with preference for inorganic pigments in a concentration offrom 0.001 to 10, preferably 0.5 to 3, % of the total weight of themixture.

Stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack.

It is also possible to add wetting agents, preservatives, disintegrants,adsorbents, release agents and propellants (cf., for example, H. Suckeret al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).

Auxiliaries include for the purpose of the invention substances forproducing a solid solution of the active ingredient. Examples of theseauxiliaries are pentaerythritol and pentaerythritol tetraacetate,polymers such as polyethylene oxides and polypropylene oxides and theirblock copolymers (poloxamers), phosphatides such as lecithin, homo- andcopolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40stearate, and citric and succinic acids, bile acids, sterols and othersas indicated, for example, in J. L. Ford, Pharm. Acta Helv. 61 (1986)69-88.

Auxiliaries are also regarded as being bases and acids added to controlthe solubility of an active ingredient (see, for example, K. Thoma etal., Pharm. Ind. 51 (1989) 98-101).

The only precondition for the suitability of auxiliaries is adequatethermal stability.

Active ingredients mean for the purpose of the invention all substanceswith a physiological effect as long as they do not decompose under theprocessing conditions. These are, in particular, pharmaceutical activeingredients (for humans and animals), active ingredients for planttreatment, insecticides, active ingredients of human and animal foods,fragrances and perfume oils. The amount of active ingredient per doseunit and the concentration may vary within wide limits depending on theactivity and the release rate. The only condition is that they sufficeto achieve the desired effect. Thus, the concentration of activeingredient can be in the range from 0.1 to 95, preferably from 20 to 80,in particular 30 to 70, % by weight. It is also possible to employcombinations of active ingredients. Active ingredients for the purposeof the invention also include vitamins and minerals. The vitaminsinclude the vitamins of the A group, the B group, by which are meantbesides B₁, B₂, B₆ and B₁₂ and nicotinic acid and nicotinamide alsocompounds with vitamin B properties such as adenine, choline,pantothenic acid, biotin, adenylic acid, folic acid, orotic acid,pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoicacid, and vitamin C, vitamins of the D group, E group, F group, H group,I and J groups, K group and P group. Active ingredients for the purposeof the invention also include therapeutic peptides. Plant treatmentagents include, for example, vinclozolin, epoxiconazole and quinmerac.

The novel process is suitable, for example, for processing the followingactive ingredients:

acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir, alprazolam,alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride,aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, cefachlor, cefalexin, cefadroxil, cefazoline,cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline,chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone,choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride,cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam,clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid,cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol,dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxycycline, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil,gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide,clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol,heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate,isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole,ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine,levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine,lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin,medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam,minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures orcombinations and mineral salts, N-methylephedrine, naftidrofuryl,naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine,nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine,nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline,nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,pantothenic acid, paracetamol, penicillin G, penicillin V,phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone,bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin,salicylic acid, simvastatin, somatropin, sotalol, spironolactone,sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride,tamoxifen, tegafur, teprenone, terazosin,. terbutaline, terfenadine,tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamicacid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,folinic acid, zidovudine.

Preferred active ingredients are ibuprofen (as racemate, enantiomer orenriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid,verapamil, paracetamol, nifedipine or captopril.

To produce the solid dosage forms, a plastic mixture of the components(melt) is prepared and then subjected to a shaping step. There arevarious ways of mixing the components and forming the melt. The mixingcan take place before, during and/or after the formation of the melt.For example, the components can be mixed first and then melted or bemixed and melted simultaneously. The plastic mixture is often thenhomogenized in order to disperse the active ingredient thoroughly.

However, it has proven preferable, especially when sensitive activeingredients are used, first to melt the polymeric binder and, whereappropriate, make a premix with conventional pharmaceutical additives,and then to mix in (homogenize) the sensitive active ingredient(s) inthe plastic phase in intensive mixers with very short residence times.The active ingredient(s) can for this purpose be employed in solid formor in solution or dispersion.

The components are generally employed as such in the production process.However, they can also be used in liquid form, ie. as solution,suspension or dispersion.

Suitable solvents for the liquid form of the components are primarilywater or a water-miscible organic solvent or a mixture thereof withwater. However, it is also possible to use organic solvents which areimmiscible or miscible with water. Suitable water-miscible solvents are,in particular, C₁-C₄-alkanols such as ethanol, isopropanol orn-propanol, polyols such as ethylene glycol, glycerol and polyethyleneglycols. Suitable water-immiscible solvents are alkanes such as pentaneor hexane, esters such as ethyl acetate or butyl acetate, chlorinatedhydrocarbons such as methylene chloride, and aromatic hydrocarbons suchas toluene and xylene. Another solvent which can be used is liquid CO₂.

The solvent used in the individual case depends on the component to betaken up and the properties thereof. For example, pharmaceutical activeingredients are frequently used in the form of a salt which is, ingeneral, soluble in water. Water-soluble active ingredients cantherefore be employed as aqueous solution or, preferably, be taken up inthe aqueous solution or dispersion of the binder. A correspondingstatement applies to active ingredients which are soluble in one of thesolvents mentioned, if the liquid form of the components used is basedon an organic solvent.

It is possible where appropriate to replace melting by dissolving,suspending, or dispersing in the above mentioned solvents, if desiredand/or necessary with the addition of suitable auxiliaries such asemulsifiers. The solvent is then generally removed to form the melt in asuitable apparatus, eg. an extruder. This will be comprised by the termmixing hereinafter.

The melting and/or mixing takes place in an apparatus customary for thispurpose. Particularly suitable ones are extruders or containers whichcan be heated where appropriate and have an agitator, eg. kneaders (likethose of the type to be mentioned below).

A particularly suitable mixing apparatus is one employed for mixing inplastics technology. Suitable apparatuses are described, for example, in“Mischen beim Herstellen und Verarbeiten von Kunststoffen”, H. Pahl,VDI-Verlag, 1986. Particularly suitable mixing apparatuses are extrudersand dynamic and static mixers, and stirred vessels, single-shaftstirrers with stripper mechanisms, especially paste mixers, multishaftstirrers, especially PDSM mixers, solids mixers and, preferably,mixer/kneader reactors (eg. ORP, CRP, AP, DTB supplied by List orReactotherm supplied by Krauss-Maffei or Ko-Kneter supplied by Buss),trough mixers and internal mixers or rotor/stator systems (eg. Dispaxsupplied by IKA).

In the case of sensitive active ingredients it is preferable first forthe polymeric binder to be melted in an extruder and then for the activeingredient to be admixed in a mixer/kneader reactor. On the other hand,with less sensitive active ingredients, a rotor/stator system can beemployed for vigorously dispersing the active ingredient.

The mixing apparatus is charged continuously or batchwise, depending onits design, in a conventional way. Powdered components can be introducedin a free feed, eg. via a weigh feeder. Plastic compositions can be fedin directly from an extruder or via a gear pump, which is particularlyadvantageous if the viscosities and pressures are high. Liquid media canbe metered in by a suitable pump unit.

The mixture obtained by mixing and/or melting the binder, the activeingredient and, where appropriate, the additive(s) ranges from pasty toviscous (plastic) or fluid and is therefore extrudable. The glasstransition temperature of the mixture is below the decompositiontemperature of all the components present in the mixture. The bindershould preferably be soluble or swellable in a physiological medium.

The steps of mixing and melting in the process can be carried out in thesame apparatus or in two or more separately operating apparatuses. Thepreparation of a premix can take place in one of the conventional mixingapparatuses described above. A premix of this type can then be feddirectly, for example, into an extruder and subsequently extruded, whereappropriate with the addition of other components.

It is possible in the novel process to employ as extruders single screwmachines, intermeshing screw machines or else multiscrew extruders,especially twin screw extruders, corotating or counterrotating and,where appropriate, equipped with kneading disks. If it is necessary inthe extrusion to evaporate a solvent, the extruders are generallyequipped with an evaporating section. Particularly preferred extrudersare those of the ZSK series from Werner & Pfleiderer.

It is also possible according to the invention to produce multilayerpharmaceutical forms by coextrusion, in which case a plurality ofmixtures of the components described above is fed together to anextrusion die so as to result in the required layered structure of themultilayer pharmaceutical form. It is preferable to use differentbinders for different layers.

Multilayer drug forms preferably comprise two or three layers. They maybe in open or closed form, in particular as open or closed multilayertablets.

At least one of the layers contains at least one pharmaceutical activeingredient. It is also possible for another active ingredient to bepresent in another layer. This has the advantage that two mutuallyincompatible active ingredients can be processed or that the releasecharacteristics of the active ingredient can be controlled.

The shaping takes place by coextrusion with the mixtures from theindividual extruders or other units being fed into a common coextrusiondie and extruded. The shape of the coextrusion die depends on therequired pharmaceutical form. Examples of suitable dies are those with aflat orifice, called a slit die, and dies with an annular orifice. Thedesign of the die depends on the polymeric binder used and the requiredpharmaceutical form.

The resulting mixture is preferably solvent-free, ie. it containsneither water nor an organic solvent.

The plastic mixture is, as a rule, subjected to final shaping. This canresult in a large number of shapes depending on the die and mode ofshaping. For example, if an extruder is used, the extrudate can beshaped between a belt and a roll, between two belts or between tworolls, as described in EP-A-358 105, or by calendering in a calenderwith two molding rolls, see, for example, EP-A-240 904. Other shapes canbe obtained by extrusion and hot- or cold-cut of the extrudate, forexample small-particle and uniformly shaped pellets. Hot-cutpelletization usually results in lenticular dosage forms (tablets) witha diameter of from 1 to 10 mm, while strip pelletization normallyresults in cylindrical products with a length to diameter ratio of from1 to 10 and a diameter of from 0.5 to 10 mm. It is thus possible toproduce monolayer but also, on use of coextrusion, open or closedmultilayer dosage forms, for example oblong tablets, coated tablets,pastilles and pellets. The resulting granules can then also be ground toa powder and compressed to tablets in a conventional way. Micropastillescan be produced by the Rotoform-Sandvik process. These dosage forms canbe rounded and/or provided with a coating by conventional methods in asubsequent process step. Examples of materials suitable for filmcoatings are polyacrylates such as the Eudragit types, cellulose esterssuch as the hydroxypropylcellulose phthalates, and cellulose ethers,such as ethylcellulose, hydroxypropylmethylcellulose orhydroxypropylcellulose.

In specific cases there may be formation of solid solutions. The termsolid solutions is familiar to the skilled worker, for example from theliterature cited at the outset. In solid solutions of active ingredientsin polymers, the active ingredient is in the form of a moleculardispersion in the polymer.

The following examples are intended to illustrate the novel processwithout restricting it, however.

EXAMPLES Example 1 Synthesis of a Graft Copolymer Consisting of 40% byWeight of an Oxygen-Containing Block Copolymer (Grafting Base) and 60%by Weight of Methyl Methacrylate (Grafted-On Monomer)

A mixture of 240 g of an ABA block copolymer (Poloxamer 188;A=polyethylene oxide block, B=polypropylene oxide block) and 440 g ofn-propanol was heated to 92° C. while stirring under a nitrogenatmosphere. After the internal temperature reached 92° C., 70 g ofmethyl methacrylate and 21 g of a mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol were added. Then, while stirringcontinuously at 92° C., 290 g of methyl methacrylate were metered inover 2 hours and the remainder of the mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol was metered in over 2.5 hours. Afterthe initiator had been fed in, the mixture was refluxed for two hoursand, after addition of a further 0.6 g of tert-butyl peroctoate,after-polymerization was carried out under reflux for 3 hours. 600 g ofwater were added, and the reaction mixture was cooled overnight. Thenext morning the n-propanol was replaced by water (steam distillation)and the precipitated product was filtered off (suction funnel) andwashed with a large amount of water. A white powder was obtained. Kvalue (1% strength in acetone): 22.9; DSC: (differential scanningcalorimetry): 1 glass transition stage at 58° C. (2nd heating cycle).

Example 2 Synthesis of a Graft Copolymer Consisting of 30% by Weight ofan Oxygen-Containing Block Copolymer (Grafting Base) and 70% by Weightof Methyl Methacrylate (Grafted-On Monomer)

A mixture of 180 g of an ABA block copolymer (Poloxamer 188;A=polyethylene oxide block, B=polypropylene oxide block) and 440 g ofn-propanol was heated to 92° C. while stirring under a nitrogenatmosphere. After the internal temperature reached 92° C., 70 g ofmethyl methacrylate and 21 g of a mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol were added. Then, while stirringcontinuously at 92° C., 350 g of methyl methacrylate were metered inover 2 hours and the remainder of the mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol was metered in over 2.5 hours. Afterthe initiator had been fed in, the mixture was refluxed for two hoursand, after addition of a further 0.6 g of tert-butyl peroctoate,after-polymerization was carried out under reflux for 3 hours. 600 g ofwater were added, and the reaction mixture was cooled overnight. Thenext morning the n-propanol was replaced by water (steam distillation)and the precipitated product was filtered off (suction funnel) andwashed with a large amount of water. A white powder was obtained. Kvalue (1% strength in acetone): 29.1; DSC: 1 glass transition stage at67° C. (2nd heating cycle).

Example 3 Synthesis of a Graft Copolymer Consisting of 20% by Weight ofan Oxygen-Containing Block Copolymer (Grafting Base) and 80% by Weightof Methyl Methacrylate (Grafted-On Monomer)

A mixture of 120 g of the ABA block copolymer from Example 1(A=polyethylene oxide block, B=polypropylene oxide block) and 440 g ofn-propanol was heated to 92° C. while stirring under a nitrogenatmosphere. After the internal temperature reached 92° C., 70 g ofmethyl methacrylate and 21 g of a mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol were added. Then, while stirringcontinuously at 92° C., 410 g of methyl methacrylate were metered inover 2 hours and the remainder of the mixture of 3 g of tert-butylperoctoate and 120 g of n-propanol was metered in over 2.5 hours. Afterthe initiator had been fed in, the mixture was refluxed for two hoursand, after addition of a further 0.6 g of tert-butyl peroctoate,after-polymerization was carried out under reflux for 3 hours. 600 g ofwater were added, and the reaction mixture was cooled overnight. Thenext morning the n-propanol was replaced by water (steam distillation)and the precipitated product was filtered off (suction funnel) andwashed with a large amount of water. A white powder was obtained. Kvalue (1% strength in acetone): 30.2; DSC: 1 glass transition stage at78° C. (2nd heating cycle).

Example 4 520 g of the Graft Copolymer from Example 1 were Extruded with480 g of Verapamil Hydrochloride, and Calendered to 1000 mg OblongTablets, Under the Following Conditions

Section 1  67° C. Section 2  98° C. Section 3 131° C. Section 4 111° C.Section 5  97° C. Die  81° C.

The release after 8 hours was 40% [USP paddle method (pH change)].

Example 5 520 g of the Graft Copolymer from Example 2 were Extruded with480 g of Verapamil Hydrochloride, and Calendered to 1000 mg OblongTablets, Under the Following Conditions

Section 1  63° C. Section 2  96° C. Section 3 131° C. Section 4 110° C.Section 5  97° C. Die  90° C.

The release after 8 hours was 45% [USP paddle method (pH change)].

Example 6 520 g of the Graft Copolymer from Example 3 were Extruded with480 g of Verapamil Hydrochloride, and Calendered to 1000 mg OblongTablets, Under the Following Conditions

Section 1  56° C. Section 2  92° C. Section 3 130° C. Section 4 112° C.Section 5 100° C. Die  90° C.

The release after 8 hours was 47% [USP paddle method (pH change)].

1. A solid dosage form which comprises at least one active ingredientand optionally one or more conventional additives, and as polymericbinder a water-swellable graft copolymer or a mixture of graftcopolymers, wherein the graft copolymer is obtained by free radicalinitiated polymerization of a) C₁-C₈-alkyl esters ofα,β-monoethylenically unsaturated C₃-C₈-mono- or -dicarboxylic acids ormixtures thereof in the presence of b) homo- or copolymers ofC₂-C₄-alkylene oxides as grafting base, and c) optionally one or moremonomers having at least two non-conjugated ethylenically unsaturateddouble bonds, wherein the graft copolymer comprises components a) and b)in a ratio of from 85 to 55: 15 to 45 by weight, and the graft copolymerhas a Fikentscher K value of from 7 to
 100. 2. The solid dosage form ofclaim 1, wherein component a) of the graft copolymer is at least oneester of acrylic acid or methacrylic acid with a C₁-C₈-alkanol.
 3. Thesolid dosage form of claim 1, wherein component b) of the graftcopolymer is a homo or copolymer of ethylene oxide, propylene oxide,n-butylene oxide or isobutylene oxide.
 4. The solid dosage form of claim1, wherein component a) is methyl methacrylate and component b) is acopolymer of ethylene oxide and propylene oxide.
 5. The solid dosageform of claim 1, wherein the Fikentscher K value is of from 20 to
 35. 6.The solid dosage form of claim 1, which is adapted as a pharmaceuticaldosage form, a fragrance formulation, a plant treatment composition, ananimal feed additive or supplement, or a human food supplement.